Therapeutic Drug Monitoring in Pharmacovigilance and Pharmacotherapy Safety

Abstract

Quantification of serum or plasma concentrations of medications is essential to find out if an adverse drug effect (ADE) is associated with an elevated drug concentration. In former years TDM was therefore often used in pharmacovigilance just to confirm that an ADE that had already occurred was due to an elevated drug plasma concentration without identifying the underlying cause for the surprising high concentration. This old approach of Therapeutic Drug Monitoring (TDM) in pharmacovigilance needs to be revised due to new developments in information technology, new analytical procedures and due to the inclusion of clinical pharmacological expert opinions in the presentation of laboratory medicine results. Today, TDM may be used to prevent ADE, rather than just confirming a suggested cause of an ADE that has happened in the past. This approach means that blood should be drawn for TDM analysis after the pharmacokinetic steady state has been reached (5 times of the elimination half life of the drug) with low to moderate dosages under the intended (poly)medication if the patient is clinically regarded as not belonging to the “normal” patient population. With the availability of reliable automated analytical methods this can be performed at a reasonable price. Funds may be saved to the health care system, because hospitalization will be thereby shortened and expensive diagnoses and treatment of ADE will be avoided. However, this has still to be proven in cross-system studies: Budget will be saved in 2 areas of the health system (hospital stay and drug costs), whereas a much smaller amount of money has to be invested for laboratory analyses in another area. TDM may thus change pharmacovigilance as a tool for monitoring and documentation of ADE to a safety tool in drug therapy for prevention of ADE.

Key words

TDM - pharmacovigilance - drug safety - pharmacotherapy safety - dose-related reference range - therapeutic reference range - KONBEST - laboratory information management system (LIMS) - 9-field board - clinical pharmacological comment - HPLC - UHPLC - quantification of drug concentration - analytical methods

• References

• 1 Berthold H, Schott G, Müller-Oerlinghausen B. und die Arzneimittelkommission der deutschen Ärzteschaft . Pharmakovigilanz: Empfehlungen zur Meldung unerwünschter Arzneimittelwirkungen durch die Ärzteschaft. Arzneiverordnung in der Praxis 2005; 32 (Supp. 1) 4-29
• 2 BMG (Bundesministerium für Gesundheit, German Federal Ministry of Health) : §63b, Gesetz über den Verkehr mit Arzneimitteln (Arzneimittelgesetz, AMG) in der Fassung der Bekanntmachung vom 12.12.2005 (BGBl. I S. 3394), zuletzt geändert durch Artikel 1 des Gesetzes zur Änderung arzneimittelrechtlicher und anderer Vorschriften vom 17. Juli 2009 (BGBl. I S. 1990)
• 3 Dandliker WB, Feigen GA. Quantification of the Antigen-Antibody-Reaction by the Polarization of Fluorescence. Biochem Res Comm 1961; 5: 299-304
• 4 Fallas MM, Neue UD, Hadley MR et al. Further investigations of the effect of pressure on retention in ultra-high-pressure liquid chromatography. J Chromatogr A 2010; 1217: 276-284
• 5 Fichtl B. Arzneistoffkonzentration im Organismus in Abhängigkeit von der Zeit: Phamakokinetik im engeren Sinn. In: Forth W, Henschler D, Rummel W, Starke K. Allgemeine und spezielle Pharmakologie und Toxikologie. Bibliographisches Institut & F.A. Brockhaus AG, Mannheim the author can trace this back and follow it over several editions. 6^th edition 1992. p 70 , to the 9^th edition 2005, p 78
• 6 German Medical Association Professional Code for Physicians in Germany (Musterberufsordnung für die deutschen Ärztinnen und Ärzte, MBO) as adopted by the 100th German Medical Assembly and amended by the 103rd German Medical Assembly, the 105th German Medical Assembly, the 106th German Medical Assembly, the 107th German Medical Assembly and the Resolution of the Council of the German Medical Association of 24.11.2006.
• 7 Greiner C, Haen E. Therapeutisches Drug Monitoring in der Psychiatrie – Erstellung von Referenzbereichen für die Dosis-Konzentrations-Beziehung. Psychiat Prax 2007; 34: S90-S92
• 8 Greiner C, Haen E. Development of a Simple Column-Switching High-Performance Liquid Chromatography (HPLC) Method for Rapid and Simultaneous Routine Serum Monitoring of Lamotrigine, Oxcarbazepine and 10-Monohydroxycarbazepine (MHD). J Chromatogr B 2007; 854: 338-344
• 9 Greiner C, Hiemke C, Bader W et al. Determination of Citalopram and Escitalopram together with Their Active Main Metabolites Desmethyl(es-)citalopram in Human Serum by Column-Switching High Performance Liquid Chromatography (HPLC) and Spectrophotometric Detection. J Chromatogr B 2007; 848: 391-394
• 10 Grohmann R, Rüther E, Schmidt LG. Unerwünschte Wirkungen von Psychopharmaka: Ergebnisse der AMÜP-Studie. Springer Verlag; Berlin: 1994
• 11 Haen E, Göpfert C Cytochrom-P450-Interaktionstabelle. accessible via www.amuep-agate.de → Arzneimittelinformationsdienst → Cytochrom-P450-Interaktionstabelle
• 12 Haen E. AGATE: Qualitätssicherung in der Psychopharmakotherapie. Neurotransmitter. 2004; 15 (7/8) 34-43
• 13 Haen E. Bedeutung der klinisch-pharmakologischen Befundung von Wirkstoffkonzentrationsmessungen zur Therapieleitung. Psychopharmakotherapie 2005; 12: 138-143
• 14 Haen E, Greiner C, Bader W et al. Wirkstoffkonzentrationsbestimmungen zur Therapieleitung – Ergänzung therapeutischer Referenzbereiche durch dosisbezogene Referenzbereiche. Der Nervenarzt 2008; 79: 558-566
• 15 Kalili KM, de Villiers A. Recent developments in the HPLC separation of phenolic compounds. J Sep Sci 2011; 34: 854-876
• 16 Köstlbacher A, Haen E. Konbest – A Web-Based Laboratory Information Management System (LIMS) for TDM-Laboratories. Pharmacopsychiatry 2008; 41: 212
• 17 Rao ML, Staberock U, Baumann P et al. Monitoring tricyclic antidepressant concentrations in serum by fluorescence polarization immunoassay compared with gas chromatography and HPLC. Clin Chem 1994; 40: 929-933
• 18 Roche Diagnostics GmbH, Mannheim/Germany . Carbamazepine detected by COBAS INTEGRA 400/700/800. Method information sheet 2008;
• 19 Roche Diagnostics GmbH, Mannheim/Germany. . Valproic Acid detected by COBAS INTEGRA 400/700/800. Method information sheet 2008;